Long-Lasting Anaesthetic Formulation

The inventive concept described herein generally relates to pharmaceutical compositions comprising an anesthetic agent. Specifically, the present inventive concept relates to a pharmaceutical composition with a long-lasting anesthetic effect, and the production of such composition.

Local anesthetic agents create an absence of pain in a specific location of the body without a loss of consciousness by reversibly inhibiting nerve impulses, causing a sensory or motor blockade. They are used to numb areas of the body when surgeries or painful examination by a physician are to be performed, or to provide pain-relief when needed. The agents may be divided into groups based on type. The ester group of local anesthetic drugs comprises benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine. The amide group of local anesthetic drugs comprises articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine and trimecaine. The drugs have the similar mechanism of action in which they cause a reversible inhibition of sodium ion influx, which blocks impulse conduction in nerve fibers.

The drugs ropivacaine and bupivacaine are highly similar, with only one methyl group difference. However, ropivacaine benefits from higher efficacy, which may partly be because ropivacaine is sold as an optionally pure S-enantiomer.

Ropivacaine is a well-tolerated anesthetic drug, effective for surgical anesthesia as well as for relief of postoperative and labor pain (Kuthiala and Chaudhary, 2011). Carbon quantum dots are a class of nanomaterials that have attracted attention because of their low toxicity, water solubility and fluorescence. As such, it has been suggested that they may prove useful in the field of imaging and drug delivery. Qu et al describe the synthesis of ibuprofen-based carbon quantum dots and show that the dots are stable, non-toxic and have good bio-combability in water. Moreover, the anti-inflammatory properties of ibuprofen were retained.

Although local anesthetic agents are effective for surgical anesthesia and relief of pain, there is room for improvement, for example pharmacokinetic (PK) or pharmacodynamic (PD) properties in the body of a mammal. Although effort has been made in the field of anesthetic products, there is still a need for improved products. Would improved products be provided, an even greater benefit for mankind would arise if such products would be long-lasting.

It is an object of the present invention to at least partly reduce or overcome challenges in the prior art, and provide means for treatment, alleviation and/or prevention of pain. These and other objects are achieved in full, or at least in part, by aspects of the inventive concepts as disclosed herein. The present inventor have surprisingly found that a pharmaceutical composition comprising at least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; at least one alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine; water; and optionally a pharmaceutically acceptable diluent, carrier and/or excipient is efficient in providing a long-lasting anesthetic effect. Thus, in a first aspect of the present invention, there is provided such pharmaceutical composition, which benefits from an increase in duration of pain relief, when compared to a similar compound that is not formulated in accordance with the inventive composition. The inventor shows that a composition according to the present invention provides increased duration of pain-relief in vivo. It is envisioned that the increased pain-relief in vivo at least partly replaces a need for opioid treatments, which is commonly used in clinical practice as postoperative rescue medication. As such, risks of complications from opioid treatment may be decreased by use of a composition according to the present invention.

In one embodiment, said at least one anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment, said at least one anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In one embodiment, said pharmaceutical composition further comprises polyethylene glycol (PEG).

Preferably, said composition comprises carbon quantum dots. Without being bound by theory, it is envisioned that the carbon quantum dots provide an increase of the therapeutic effect or provide improved pharmacokinetic and/or pharmacodynamic properties of an anesthetic agent in the inventive composition. Without being bound by theory, such an increase may be the result of increased water solubility; or increased cellular internalization of the anesthetic agent; or that said anesthetic agent is associated with said carbon quantum dot for a period of time, thus providing a slow-release effect of said anesthetic agent. In one embodiment, said carbon quantum dots comprises said at least one anesthetic agent. In one embodiment, said carbon quantum dots comprise at least one of said alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine. In one embodiment, said carbon quantum dots comprise triethanolamine.

In one embodiment, said carbon quantum dots further comprises PEG. In one embodiment, said PEG is located on the surface of said carbon quantum dots.

Several routes of administration are envisioned. In one embodiment, said composition is formulated to be administrated by injection or by topical administration.

In one embodiment, said composition is formulated to be administrated as a nerve block in lower and upper extremities, intraarticular in various joints, subcutaneous, intrathecal. Preferably, administration is not intravenous administration.

In one embodiment, said administration is by topical administration, such as by a patch, a cream, a gel or by a spray. Such administration may be beneficial since use of a topical composition may not require a medicinal practitioner to apply said pharmaceutical composition. As such, a subject in need of anesthesia may self-administer the composition to herself or himself. Self-administration has the advantage of allowing a patient to adjust the dose or the frequency of medication either according to a subjective evaluation of their condition or according to a schedule prescribed by a treating physician. The term “schedule prescribed by the treating physician” includes the alternative where a patient makes a subjective evaluation of his/her condition, either unaided or aided by a questionnaire or a range or scale, or using an algorithm or a computer program, indicating the suitable next dose.

Percutaneous administration, using the composition according to the present invention formulated as a cream, a gel, and an ointment or in the form of adhesive medicine patches, is another possible form of administration, similarly suitable for self-administration. The advantages of self-administration listed above apply also to percutaneous administration, with the added advantage that the administration can easily be interrupted if desired or necessary, e.g. by removing the medicine patch.

When the topical composition is in the form of a patch, a gel or a spray said composition may comprise additional ingredients. The skilled person understands what additional ingredients are suitable for the specific topical use. For example, a spray may need the addition of a propellant. Suitable propellants are apparent to the skilled person. A lotion, a skin cream or an ointment may need the addition of an emollient. Suitable emollients are apparent to the skilled person.

A gel may need the addition of a gelifying agent such as a gelifying polymer. Suitable polymers are apparent to the skilled person. For example, cellulose, such as a nonionic water-soluble cellulose ethers. In addition, a gel may comprise an alcohol, such as a C1-C4 alcohol, such as a C1-C3 alcohol or a C2-C4 alcohol, such as ethanol.

In addition, a gel may comprise benzyl alcohol. In some embodiments, the gel comprises Ropivacaine and Lidocaine. In some embodiments, the gel comprises ropivacaine and lidocaine, benzyl alcohol, ethanol and Klucel MFX. In addition, the gel may comprise Sodium Borate (Borax). An example of a gel comprising ropivacaine and lidocaine is described in Example 5.

A patch may comprise an additional agent and may comprise more than one local anesthetic agent. In one embodiment, when the topical composition is in the form of a patch, the composition comprises at least one of bupivacaine and ropivacaine, and furthermore lidocaine, such as that the composition comprises ropivacaine and lidocaine.

It is also possible that the composition is administered via a depot formulation, which releases an effective amount of the anesthetic agent as disclosed herein, over a period of time. The skilled person will appreciate that the depot formulation may be adapted to deliver the desired effective dose as prescribed by a treating physician. A depot formulation may be a subcutaneous depot formulation. Thus, in one embodiment, said administration is via a depot formulation, such as a subcutaneous depot formulation.

In one embodiment, said administration is by injection, such as by parenteral injection or by subcutaneous injection. In one embodiment, said administration is as a single injection. Because of the long lasting effect of the inventive composition, a single injection may be suitable when administering the composition of the invention, which may be time-efficient.

Conventionally used excipients for intravenous administration are for example sterile water for injections (WFI), sterile buffers (for example buffering the solution to pH 7.4), an albumin solution, lipid solutions, cyclodextrin and variants thereof, and the like. Conventionally used excipients for subcutaneous administration are for example sterile water for injections (WFI), sterile buffers (for example buffering the solution to pH 7.4), lipid solutions, cyclodextrins and the like. Conventionally used excipients for subcutaneous administration via a subcutaneous delivery system, such as a subcutaneous rod, are for example sterile water for injections (WFI), sterile buffers (for example buffering the solution to pH 7.4), lipid solutions, cyclodextrins and the like.

Conventionally used excipients for transdermal and/or subcutaneous administration are for example vaseline, liquid paraffin, glycerol, water, MCT oil, sesame oil and the like.

The skilled person will appreciate that the suitable dose will naturally vary depending on the mode of administration, the particular condition to be treated or the effect desired, gender, age, weight and health of the patient, as well as possibly other factors, evaluated by the treating physician. In one embodiment, the dose of said anesthetic agent is a single dose (a unit dose) of from 5 to 600 mg, such as from 10 to 500 mg, such as from 20 to 450 mg, such as from 50 to 400 mg, such as from 100 to 400 mg, such as from 200 to 350 mg, such as from 200 to 300 mg.

In one embodiment, the concentration of said anesthetic agent is at a dose of 1-20 mg/ml, such at a dose of 2-15 mg/ml, such as at a dose of 5-10 mg/ml, such as at a dose of 5 mg/ml of said composition. Commonly used doses are 2.5 mg/ml; 5 mg/ml; 7.5 mg/ml, 10 mg/ml; 20 mg/ml; 30 mg/ml; and is dependent on the specific anesthetic agent used as well as the specific conditions.

In one embodiment, the concentration of said alkanolamine in the composition is within the range of 0.1-20 M (mol/dm), such as within the range of 0.2-18 M, such as within the range of 0.2-18 M, such as within the range of 0.5-15 M, such as within the range of 1-12 M, such as within the range of 2-10 M, such as within the range of 3-8 M, such as within the range of 4-6 M, such around 5 M.

In one embodiment, the concentration of said anesthetic agent in the composition is within the range of 0.1-500 mM (mol/dm), such as within the range of 1-400 mM, such as within the range of 100-300 mM, such as within the range of 220-260 mM, such as within the range of 240-250 mM, such as around 245 mM.

In one embodiment, the concentration of PEG is around 0.1-100 μM, such as around 1-50 μM, such as around 5-15 μM, such as around 8 μM.

A composition of the invention may be prepared with different ratios of the components therein. For example, in one embodiment, there is a molar ratio of alkanolamine to anesthetic agent in the composition that is at least 2:1, such as at least 3:1, such as at least 4:1, such as at least 5:1, such as at least 6:1, such as at least 7:1, such as at least 8:1, such as at least 9:1, such as at least 10:1, such as at least 11:1, such as at least 12:1, such as at least 13:1, such as at least 14:1, such as at least 15:1, such as at least 16:1, such as at least 17:1, such as at least 18:1, such as at least 19:1, such as at least 20:1, such as at least 21:1, such as at least 22:1, such as at least 23:1, such as at least 24:1, such as at least 25:1.

A composition of the invention may be prepared with different pH values. For example, in one embodiment the pH of the composition is from pH 5 to pH 8, such as around pH 5, or such as around pH 5.5, or such as around pH 6, or such as around pH 6.5, or such as around pH 7, or such as around pH 7.5.

As discussed above, the present invention provides a formulation comprising at least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, procaine, proparacaine, tetracaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, chloroprocaine, cocaine, procaine, proparacaine and tetracaine.

In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, chloroprocaine, cocaine, procaine, proparacaine and tetracaine. In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, chloroprocaine, procaine, proparacaine and tetracaine.

In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine and prilocaine. In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, etidocaine, mepivacaine and prilocaine. In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine, mepivacaine and prilocaine. In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine and prilocaine. In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine and mepivacaine. In one embodiment, said least one anesthetic agent selected from the group consisting of ropivacaine, bupivacaine and etidocaine. In one embodiment, said anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine and lidocaine. In one embodiment, said least one anesthetic agent is a combination of ropivacaine and lidocaine. In one embodiment, said least one anesthetic agent is a combination of bupivacaine and lidocaine. In one embodiment, said anesthetic agent is selected from the group consisting of ropivacaine and bupivacaine. In one embodiment, said anesthetic agent is bupivacaine. For the sake of clarity, the chemical formula of bupivacaine is presented as formula I below:

In one embodiment, said anesthetic agent is lidocaine. For the sake of clarity, the chemical formula of lidocaine is presented as formula II below:

In one embodiment, said anesthetic agent is ropivacaine. For the sake of clarity, the chemical formula of ropivacaine is presented as formula III below:

In one embodiment, when said anesthetic agent is ropivacaine, said ropivacaine is in alkaline form. In one embodiment, said ropivacaine is present as a hydrochloride salt. Other pharmaceutically acceptable salts are also envisioned as suitable in the composition.

The skilled person appreciates that pharmaceutically acceptable salts of a anesthetic agent in accordance with this aspect of the present disclosure, are suitable to use in the composition. Salts which are suitable for use in medicine are those wherein a counterion is pharmaceutically acceptable. Examples of such pharmaceutically acceptable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkane-carboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C1-C4)alkyl or aryl sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine.

In one embodiment, ropivacaine is present in its S-enantiomeric form. Preferably, S-ropivacaine may be present in enantiomeric excess. Such excess still allows R-ropivacaine to be present, however in a smaller amount compared to the S-form. The composition may comprise PEG. In one embodiment, said PEG is selected from the group consisting of PEG-3350, PEG-4000, PEG-6000, PEG-8000 and PEG-10000. In one embodiment, said PEG is PEG-3350 or PEG-4000. In one preferred embodiment, said PEG is PEG-4000.

The composition according to the present invention comprises water. The water may be purified water that is suitable for pharmaceutical applications. The water may be sterile water for injections (WFI). The water may be deionized water (diHO). The water may be distilled water (dHO). In one embodiment, said water is distilled water. Said distilled water may be MilliQ water. In one embodiment, said water is deionized water.

In one embodiment, the composition consists of:

In one embodiment, the composition consists of:

In one embodiment, there is a molar ratio of triethanolamine to ropivacaine in the composition that is at least 2:1, such as at least 3:1, such as at least 4:1, such as at least 5:1, such as at least 6:1, such as at least 7:1, such as at least 8:1, such as at least 9:1, such as at least 10:1, such as at least 11:1, such as at least 12:1, such as at least 13:1, such as at least 14:1, such as at least 15:1, such as at least 16:1, such as at least 17:1, such as at least 18:1, such as at least 19:1, such as at least 20:1, such as at least 21:1, such as at least 22:1, such as at least 23:1, such as at least 24:1, such as at least 25:1.

In one embodiment, the concentration of triethanolamine in the composition is within the range of 0.1-20 M (mol/dm), such as within the range of 0.2-18 M, such as within the range of 0.2-18 M, such as within the range of 0.5-15 M, such as within the range of 1-12 M, such as within the range of 2-10 M, such as within the range of 3-8 M, such as within the range of 4-6 M, such around 5 M.

In one embodiment, the concentration of ropivacaine in the composition is within the range of 0.1-500 mM (mol/dm), such as within the range of 1-400 mM, such as within the range of 100-300 mM, such as within the range of 220-260 mM, such as within the range of 240-250 mM, such as around 245 mM.

The composition may be suitable for storage, such as long-time storage. The composition may benefit from retained stability over time. In one embodiment, said composition remains stable upon storage for at least 1 day, such as for at least 1 week, such as for at least 2 weeks, such as for at least 3 weeks, such as for at least 4 weeks, such as for at least 5 weeks, such as for at least 6 weeks, such as for at least 7 weeks, such as for at least 8 weeks, such as for at least 9 weeks, such as for at least 10 weeks, such as for at least 3 months, such as for at least 6 months, such as for at least 1 year, such as for at least 2 years. For example, composition 1 and 2 of example 1 were subsequently used in example 3. Example 3 shows that the compositions were stable over a longer period of time and at different temperatures.

In one embodiment, said composition benefits from thermal stability. As such, said composition may remain thermally stable upon storage at a temperature of at least 4° C., such as at least 7° C., such as at least 10° C., such as at least 15° C., such as at least 20° C., such as at least 25° C., such as at least 30° C., such as at least 35° C., such as at least 40° C.